The incidence of melanoma has increased 600 percent over the last four decades; it is the most rapidly increasing malignancy among young people in the United States and is currently the leading cause of cancer death in women aged 25-29. If detected early, the disease is easily treated, however, once the disease has metastasized it is largely refractory to conventional therapies and is associated with a high mortality rate. The increased incidence of melanoma, combined with the poor prognosis of patients with advanced disease, make it imperative that we increase our understanding of the underlying genetic causes of melanoma such that better targeted therapeutic strategies can be developed. The sequencing of the human genome and the development of gene expression microarray technologies have resulted in the identification of hundreds of genes whose expression is modified in human cancers. While a vast amount of knowledge has been gained about genes with altered expression in tumors, relatively little is known about which of these genes are causally associated with tumor development and which represent only markers for the disease. Because of the great costs associated with the development of new therapies, it is essential that better pre-clinical models are developed to validate which genetic alterations can be productively targeted for therapeutic intervention. This proposal strives to fulfill this need by describing the development of a mouse model of melanoma based on the RCAS/TVA retroviral vector system. We have generated Ink4a/Arf lox/lx mice that express the retroviral receptor TVA specifically in melanocytes from the dopachrome tautomerase (DCT) promoter and propose to utilize retroviral vectors containing Cre-recombinase and NRas(Q61R) to induce melanoma in DCJ-T\/A/lnk4a/Arf l*/l* mice. We will use this model system to identify and validate novel genes responsible for melanoma progression and metastasis. Genes that can be targeted therapeutically will be identified by downregulating their expression using a tetracycline-responsive retrovirus or a retrovirus capable of reducing gene expression via RNA interference. Our long-term goals are to translate the knowledge gained from these studies into improvements in molecular targeted therapies for the treatment of advanced melanoma and to use this system as a pre-clinical model for future studies of drug efficacy. Relevance. The increasing incidence of melanoma, in particular among young to middle-aged adults, is a significant public health problem. The long-term goal of this research is to use this technology to identify key proteins required for the survival of melanoma cells that could serve as potential targets for the development of more effective drugs for the treatment of advanced stage melanoma.